Tranexamic acid

Background & objectives: Antifibrinolytic agents are used commonly in adult cardiac surgery to reduce postoperative blood loss. Paucity of literature on the use of a newer antifibrinolytic agent tranexamic acid (TA) in children undergoing cardiac surgery promoted us to conduct this study in children with cyanotic heart disease.

Methods: One hundred and twenty consecutive children with cyanotic heart disease were randomised into two groups. Control (group A) (n=24) given no drug while the study (group B, n=96) group was given tranexamic acid 10 mg/kg each after anaesthetic induction, on bypass and after protamine at the end of bypass. Postoperatively, total mediastinal chest tube drainage and blood and blood product usage at 24 h were recorded. Tests of coagulation including activated clotting time, fibrinogen, fibrin degradation products and platelet count were performed at 6 h postoperatively.

Results: The two groups were comparable in terms of demographic characteristics such as age, sex, weight, operations performed, and preoperative haematocrit. Postoperatively, group B, had a significantly (P

Interpretation & conclusion: Tranexamine acid was highly effective in reducing post-operative blood loss, blood and blood product usage in children with congenital cyanotic heart disease undergoing corrective surgery.

Key words Antifibrinolytics - blood loss - cardiac surgery - paediatric - postoperative - tranexamic acid

Reducing the use of homologous blood and blood products continues to be an important focus of attention in the field of cardiac surgery1, given the increased awareness of blood-borne diseases and problems due to multiple donor transfusions, frequently required in cardiac surgery. The search for various methods and pharmacological agents to reduce blood loss after cardiac surgery is ongoing. Many abnormalities of the coagulation system occur after cardiac surgery, including thrombocytopaenia, thrombocytopathy, decreased clotting factors, increase in fibrinolysis and disseminated intravascular coagulation2,3. Antifibrinolytic agents such as aprotinin and epsilon amino caproic acid (EACA) have been used to reduce blood loss after cardiac surgery in children4,5. These studies found antifibrinolytics like EACA to be more effective in cyanotic children than in non-cyanotic children.

Tranexamic acid (TA) is a newer and better antifibrinolytic agent than EACA6. In adult patients TA has been used to reduce postoperative blood loss after cardiac surgery7,8. However, there is not much information available on its use in children9. As antifibrinolytics are more beneficial in congenital cyanotic heart disease, and TA is a better agent than EACA, an attempt was made to study use of TA in cyanotic children undergoing cardiac surgery on cardiopulmonary bypass (CPB).

Material & Methods

This prospective study was done over a 9 month period from September 2002 at the Cardiothoracic & Neurosciences (CN) Centre of the all India Institute of Medical Sciences, (AIlMS), New Delhi. One hundred and twenty consecutive children with cyanotic congential heart diesease, undergoing corrective surgery were included in the study. Patients with renal impairment, previous neurological events or congenital bleeding disorders were excluded from the study. Those on heparin or aspirin were included to see the beneficial effect of TA if any, in these patients. The patients were randomized into two groups by asking the parents to pick up one of the two envelops labelled A or B. Group A was control group with no drug. Group B was the study group and children were given TA (Trxamic, Systopic, Labs, New Delhi) in a 10 mg/kg dose after anaesthetic induction followed by 10 mg/kg on CPB, and 10 mg/kg after protamine reversal of heparin. Conduct of anaesthesia and bypass was standardized in both the groups, and was similar in all respects except for the administration of TA. All operations were performed by the same surgical team, ruling out variations in surgical technique as a cause of varying postoperative blood loss. Anaesthesia was induced with ketamine (Neon, Labs, Vadodra). midazolam (Neon Labs, Vadodara), and pancuronium, (Organon Ltd., Mumbai) for muscle relaxation and maintained on air, oxygen with isoflurane (ICI Labs, Chennai) and fentanyl, (Sun Pharma, Delhi) for analgesia. CPB was conducted on all patients using a membrane oxygenator (Minimax, Medtronic, Anaheim USA), and moderate hypothermia (28°C), with non-occlusive roller pumps. The bypass circuit was primed with ringer lactate solution 20 ml/kg, sodium bicarbonate 7.5 per cent (w/v) 1 ml/kg, mannitol 20 per cent (w/v) 0.5 g/kg and heparin 100 U/kg. Blood was added if haematocrit on bypass fell below 24 per cent. Blood remaining in CPB circuit after bypass was processed through a cell saver for re-transfusion. Time taken from protamine administration to closure of the sternotomy (sternal closure time) was recorded as an indirect assessment of the coagulation status. Postoperative care was done by a separate team of intensivists blinded to the study groups, who managed postoperative bleeding and blood and blood products administration according to existing protocols. Postoperative cumulative blood loss was recorded at 24 h. Use of blood and blood products was also noted at 24 h postoperatively. Blood samples for tests of coagulation were collected at 6 h postoperatively, including activated clotting time, fibrinogen, fibrin degradation products and platelet count. Re-exploration rates in both groups were noted as also any complications referable to renal, cerebral thrombosis. The ethics committee of the institute approved this study and informed consent was obtained from the parents of children. New results were analyzed by the Student's t-test, and a P value of

Results

The two groups A and B were comparable in terms of age of the children range (2 months to 14.5 yr) weight and body surface area (Table I). The various operations performed on these patients were corrective operations for cyanotic heart disease such as tetralogy of Fallot. tricuspid atresia, pulmonary atresia and transposition of great vessels. The number of patients for various operations are : tetralogy of Fallot ( 16 in group A and 67 in group B), modified fontan operation, (4 in group A and 21 in group B), and senning operation (4 in group A and 8 in group B). Although CPB times were similar in the two groups, sternal closure time was significantly (P

Discussion

Platelet dysfunction and fibrinolysis are important causes of increased postoperative blood loss after cardiac surgery done on CPB10. As children with congenital cyanotic heart disease have a deranged coagulation system with a pre-existing altered platelet function and enhanced fibrinolysis, they are more prone to increased postoperative blood loss11, as these pre-existing defects are worsened by CPB. Patients with congenital cyanotic heart disease undergoing CPB, are known to benefit from use of antifibrinolytics such as EACA which has been used in several studies to reduce blood loss postoperatively after cardiac surgery12,13. TA is a synthetic lysine analogue, 10 times more potent as an antifibrinolytic agent than EACA. Its binding to plasminogen is much more effective than EACA5. Zonis et al9 used TA in 88 children undergoing cardiac surgery with CPB and found TA in a single dose of 50mg/kg to significantly reduce postoperative blood loss in cyanotic children. It was not found useful in reducing blood loss in acyanotic children or in reoperation. Eevine et al14, studied haemostatic parameters including platelet activation in paediatric patients but did not find TA to affect platelet function markers which were altered by CPB in cyanotic patients. The authors were unable to explain this result, but blamed changed surgeons and blood product formulations for the discrepancy14. In the present study, all operations were performed by one surgeon, avoiding variation in surgical technique as a cause of altered blood loss. Reid et al15 studied TA in 41 children undergoing reoperations with CPB and found TA in a dose of 100 mg/kg followed by a 10mg/kg/h infusion, to be effective in reducing postoperative blood loss after repeat cardiac surgery, but this study had only 11 cyanotic patients. Our study was conducted on 120 children with cyanotic heart disease given TA divided in 3 doses before, during and after CPB. Such a dose provides more uniform anti-fibrinolytic effect, as the maximum requirement forantifibrinolysis is during CPB, when peak stimulation of the fibrinolytic system occurs. Similar effect was shown by Morrow et al16 who compared a full dose of TA (10 mg/kg) followed by a 1 mg/kg/h infusion compared to a half dose (5mg/kg) with 0.5 mg/kg/h infusion, a quarter dose (2.5 mg/kg) with 0.25 mg/kg/h infusion and a double dose (20 mg/kg) and an infusion of 2 mg/kg/h, and found the double dose of TA to be the most effective.

To conclude, this study shows that TA effectively reduces postoperative blood loss and blood and blood product requirements in children with congenital cyanotic heart disease undergoing corrective surgery on CPB, with preservation of fibrinogen and lower fibrin degradation products and lower re-exploration rates, as compared to the control group.

References

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Sandeep Chauhan, Akshay Bisoi*, Rakesh Modi, Parag Gharde & M.R. Rajesh*

Departments of Cardiac Anaesthesia & * Surgery, Cardiothoracic Centre, All India Institute of Medical Sciences New Delhi, India

Received June 3, 2003

Reprint requests : Dr Sandcep Chauhan, Assistant Professor, Department of Cardiac Anaesthesia, CN Centre All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India e-mail : sdeep 61@yahoo.com

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